The invention relates to treatment of heart failure and methods for reducing fibrosis, particularly cardiac fibrosis.
Heart failure is a major cause of morbidity and mortality that affects over 24 million individuals worldwide (Rosamond et al., Circulation 117:e25-146, 2008, Cowie et al., Eur. Heart. J. 18:208-25, 1997, Davies et al., Lancet 358:439-44, 2001). Irrespective of the injurious mechanism, a decline in left ventricular (LV) function leads to increased LV volume and pressure overload. This hemodynamic stimulus activates several signaling cascades, which alter cardiac structure and function, a process known as cardiac remodeling. Persistent hemodynamic overload leads to cardiomyocyte hypertrophy and interstitial fibrosis, followed by myocyte necrosis and worsening replacement fibrosis. At each phase of cardiac remodeling from acute load to compensatory hypertrophy, various signaling cascades are implicated (Berk et al., J. Clin. Invest. 117:568-75, 2007).